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排序方式: 共有575条查询结果,搜索用时 46 毫秒
41.
Rebecca A. Capel Emma L. Bolton Wee K. Lin Daniel Aston Yanwen Wang Wei Liu Xin Wang Rebecca-Ann B. Burton Duncan Bloor-Young Kai-Ting Shade Margarida Ruas John Parrington Grant C. Churchill Ming Lei Antony Galione Derek A. Terrar 《The Journal of biological chemistry》2015,290(50):30087-30098
Ca2+-permeable type 2 two-pore channels (TPC2) are lysosomal proteins required for nicotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca2+ release in many diverse cell types. Here, we investigate the importance of TPC2 proteins for the physiology and pathophysiology of the heart. NAADP-AM failed to enhance Ca2+ responses in cardiac myocytes from Tpcn2−/− mice, unlike myocytes from wild-type (WT) mice. Ca2+/calmodulin-dependent protein kinase II inhibitors suppressed actions of NAADP in myocytes. Ca2+ transients and contractions accompanying action potentials were increased by isoproterenol in myocytes from WT mice, but these effects of β-adrenoreceptor stimulation were reduced in myocytes from Tpcn2−/− mice. Increases in amplitude of L-type Ca2+ currents evoked by isoproterenol remained unchanged in myocytes from Tpcn2−/− mice showing no loss of β-adrenoceptors or coupling mechanisms. Whole hearts from Tpcn2−/− mice also showed reduced inotropic effects of isoproterenol and a reduced tendency for arrhythmias following acute β-adrenoreceptor stimulation. Hearts from Tpcn2−/− mice chronically exposed to isoproterenol showed less cardiac hypertrophy and increased threshold for arrhythmogenesis compared with WT controls. Electron microscopy showed that lysosomes form close contacts with the sarcoplasmic reticulum (separation ∼25 nm). We propose that Ca2+-signaling nanodomains between lysosomes and sarcoplasmic reticulum dependent on NAADP and TPC2 comprise an important element in β-adrenoreceptor signal transduction in cardiac myocytes. In summary, our observations define a role for NAADP and TPC2 at lysosomal/sarcoplasmic reticulum junctions as unexpected but major contributors in the acute actions of β-adrenergic signaling in the heart and also in stress pathways linking chronic stimulation of β-adrenoceptors to hypertrophy and associated arrhythmias. 相似文献
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Threadgill DW Miller DR Churchill GA de Villena FP 《ILAR journal / National Research Council, Institute of Laboratory Animal Resources》2011,52(1):24-31
The mouse is the most extensively used mammalian model for biomedical and aging research, and an extensive catalogue of laboratory resources is available to support research using mice: classical inbred lines, genetically modified mice (knockouts, transgenics, and humanized mice), selectively bred lines, consomics, congenics, recombinant inbred panels, outbred and heterogeneous stocks, and an expanding set of wild-derived strains. However, these resources were not designed or intended to model the heterogeneous human population or for a systematic analysis of phenotypic effects due to random combinations of uniformly distributed natural variants. The Collaborative Cross (CC) is a large panel of recently established multiparental recombinant inbred mouse lines specifically designed to overcome the limitations of existing mouse genetic resources for analysis of phenotypes caused by combinatorial allele effects. The CC models the complexity of the human genome and supports analyses of common human diseases with complex etiologies originating through interactions between allele combinations and the environment. The CC is the only mammalian resource that has high and uniform genomewide genetic variation effectively randomized across a large, heterogeneous, and infinitely reproducible population. The CC supports data integration across environmental and biological perturbations and across space (different labs) and time. 相似文献
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W.?Charles?KerfootEmail author Foad?Yousef Martin?M.?Hobmeier Ryan?P.?Maki S.?Taylor?Jarnagin James?H.?Churchill 《Biological invasions》2011,13(11):2513-2531
The spiny water flea (Bythotrephes longimanus) is spreading from Great Lakes coastal waters into northern inland lakes within a northern temperature-defined latitudinal
band. Colonization of Great Lakes coastal embayments is assisted by winds and seiche surges, yet rapid inland expansion across
the northern states comes through an overland process. The lack of invasions at Isle Royale National Park contrasts with rapid
expansion on the nearby Keweenaw Peninsula. Both regions have comparable geology, lake density, and fauna, but differ in recreational
fishing boat access, visitation, and containment measures. Tail spines protect Bythotrephes against young of the year, but not larger fish, yet the unusual thick-shelled diapausing eggs can pass through fish guts
in viable condition. Sediment traps illustrate how fish spread diapausing eggs across lakes in fecal pellets. Trillions of
diapausing eggs are produced per year in Lake Michigan and billions per year in Lake Michigamme, a large inland lake. Dispersal
by recreational fishing is linked to use of baitfish, diapausing eggs defecated into live wells and bait buckets, and Bythothephes snagged on fishing line, anchor ropes, and minnow seines. Relatively simple measures, such as on-site rinsing of live wells,
restricting transfer of certain baitfish species, or holding baitfish for 24 h (defecation period), should greatly reduce
dispersal. 相似文献
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Listeria monocytogenes is an emerging foodborne pathogen that is responsible for about 28% of the food-related deaths in the United States. It causes
meningitis, septicaemia and in pregnant women, abortions and stillbirths. It secretes the toxin listeriolysin O (LLO) that
allows the bacteria to enter the cytoplasm of host cells, where they can replicate and cause further infection. The rapid
and sensitive detection of LLO in food samples is a key to monitoring and prevention of listeriosis. To facilitate the development
of an assay for the specific detection of LLO, a source of LLO is essential. We outline a method of producing a large amount
of functional LLO by expressing the hlyA gene (encoding LLO) in Escherichia coli and purifying the recombinant LLO using a one-step purification method. Purification of the protein takes only about 4 h.
We compared three different expression constructs for the production of the toxin, which tends to interact strongly with a
number of column surfaces. The first construct, using an intein fusion system, could not be purified from the column. The
second LLO construct contained an N-terminus His tag; it gave a yield of 3.5–8 mg l−1. The third contained a C-terminus His tag; it gave a yield of 2.5 mg l−1 LLO. The purified LLO from the latter two constructs retained its activity at 4°C for over a year as determined by bovine
red blood cell hemolysis assay. This paper provides a much-needed, high-yield, one-step purification method of recombinant
LLO, and is the first to provide evidence of long-term stability of the toxin for further applications. 相似文献
48.
We examine the efficiency of different genotyping and phenotyping strategies in inbred line crosses from an information perspective. This provides a mathematical framework for the statistical aspects of QTL experimental design, while guiding our intuition. Our central result is a simple formula that quantifies the fraction of missing information of any genotyping strategy in a backcross. It includes the special case of selectively genotyping only the phenotypic extreme individuals. The formula is a function of the square of the phenotype and the uncertainty in our knowledge of the genotypes at a locus. This result is used to answer a variety of questions. First, we examine the cost-information trade-off varying the density of markers and the proportion of extreme phenotypic individuals genotyped. Then we evaluate the information content of selective phenotyping designs and the impact of measurement error in phenotyping. A simple formula quantifies the information content of any combined phenotyping and genotyping design. We extend our results to cover multigenotype crosses, such as the F(2) intercross, and multiple QTL models. We find that when the QTL effect is small, any contrast in a multigenotype cross benefits from selective genotyping in the same manner as in a backcross. The benefit remains in the presence of a second unlinked QTL with small effect (explaining <20% of the variance), but diminishes if the second QTL has a large effect. Software for performing power calculations for backcross and F(2) intercross incorporating selective genotyping and marker spacing is available from http://www.biostat.ucsf.edu/sen. 相似文献
49.
Frederick B. Churchill 《Journal of the history of biology》2010,43(4):767-800
This paper examines the contents and institutional context of August Weismann’s long essay on Amphimixis (1891). Therein he presented detailed discussions of his on-going studies of reduction division and parthenogenesis, but
more to the point, he included an elaborate examination of émile Maupas’s two major publications in protozoology. To understand
the relevance of this part to the other two, the author briefly reviews highpoints in earlier nineteenth century protozoology
and concludes that only in the mid-1870s and 1880s did protozoa add an important dimension to heredity theory. Otto Bütschli
and then Maupas provided Weismann with a deeper understanding of how conjugation and fertilization were related but not identical
processes. This allowed him to integrate the two into a fuller understanding of evolution by natural selection. 相似文献
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